Fibrinogen Activates BMP Signaling in Oligodendrocyte Progenitor Cells and Inhibits Remyelination after Vascular Damage

Mark A Petersen; Jae Kyu Ryu; Kae-Jiun Chang; Ainhoa Etxeberria; Sophia Bardehle; Andrew S Mendiola; Wanjiru Kamau-Devers; Stephen P J Fancy; Andrea Thor; Eric A Bushong; Bernat Baeza-Raja; Catriona A Syme; Michael D Wu; Pamela E Rios Coronado; Anke Meyer-Franke; Stephanie Yahn; Lauriane Pous; Jae K Lee; Christian Schachtrup; Hans Lassmann; Eric J Huang; May H Han; Martina Absinta; Daniel S Reich; Mark H Ellisman; David H Rowitch; Jonah R Chan; Katerina Akassoglou

doi:10.1016/j.neuron.2017.10.008

Fibrinogen Activates BMP Signaling in Oligodendrocyte Progenitor Cells and Inhibits Remyelination after Vascular Damage

Neuron. 2017 Dec 6;96(5):1003-1012.e7. doi: 10.1016/j.neuron.2017.10.008. Epub 2017 Nov 2.

Authors

Mark A Petersen¹, Jae Kyu Ryu², Kae-Jiun Chang³, Ainhoa Etxeberria³, Sophia Bardehle², Andrew S Mendiola², Wanjiru Kamau-Devers⁴, Stephen P J Fancy⁵, Andrea Thor⁶, Eric A Bushong⁶, Bernat Baeza-Raja², Catriona A Syme², Michael D Wu⁷, Pamela E Rios Coronado², Anke Meyer-Franke², Stephanie Yahn⁸, Lauriane Pous⁹, Jae K Lee⁸, Christian Schachtrup¹⁰, Hans Lassmann¹¹, Eric J Huang¹², May H Han¹³, Martina Absinta¹⁴, Daniel S Reich¹⁴, Mark H Ellisman¹⁵, David H Rowitch¹⁶, Jonah R Chan³, Katerina Akassoglou¹⁷

Affiliations

¹ Gladstone Institutes, San Francisco, CA, USA; Department of Pediatrics, University of California, San Francisco, CA, USA.
² Gladstone Institutes, San Francisco, CA, USA.
³ Department of Neurology, University of California, San Francisco, CA, USA.
⁴ Gladstone Institutes, San Francisco, CA, USA; Berkeley City College, Berkeley, CA, USA.
⁵ Department of Pediatrics, University of California, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, CA, USA; Newborn Brain Research Institute, University of California, San Francisco, CA, USA.
⁶ National Center for Microscopy and Imaging Research, Center for Research in Biological Systems, University of California, San Diego, La Jolla, CA, USA.
⁷ Gladstone Institutes, San Francisco, CA, USA; Department of Anesthesia, University of California, San Francisco, CA, USA.
⁸ Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
⁹ Faculty of Biology, University of Freiburg, Freiburg, Germany.
¹⁰ Institute of Anatomy and Cell Biology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
¹¹ Center for Brain Research, Medical University of Vienna, Vienna, Austria.
¹² Department of Pathology, University of California, San Francisco, CA, USA.
¹³ Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
¹⁴ Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
¹⁵ National Center for Microscopy and Imaging Research, Center for Research in Biological Systems, University of California, San Diego, La Jolla, CA, USA; Department of Neurosciences, University of California, San Diego, La Jolla, California, USA; Salk Institute for Biological Studies, La Jolla, San Diego, California, USA.
¹⁶ Department of Pediatrics, University of California, San Francisco, CA, USA; Department of Neurosurgery, Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine, University of California, San Francisco, CA, USA; Department of Paediatrics, University of Cambridge, Cambridge, UK.
¹⁷ Gladstone Institutes, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, CA, USA. Electronic address: kakassoglou@gladstone.ucsf.edu.

Abstract

Blood-brain barrier (BBB) disruption alters the composition of the brain microenvironment by allowing blood proteins into the CNS. However, whether blood-derived molecules serve as extrinsic inhibitors of remyelination is unknown. Here we show that the coagulation factor fibrinogen activates the bone morphogenetic protein (BMP) signaling pathway in oligodendrocyte progenitor cells (OPCs) and suppresses remyelination. Fibrinogen induces phosphorylation of Smad 1/5/8 and inhibits OPC differentiation into myelinating oligodendrocytes (OLs) while promoting an astrocytic fate in vitro. Fibrinogen effects are rescued by BMP type I receptor inhibition using dorsomorphin homolog 1 (DMH1) or CRISPR/Cas9 activin A receptor type I (ACVR1) knockout in OPCs. Fibrinogen and the BMP target Id2 are increased in demyelinated multiple sclerosis (MS) lesions. Therapeutic depletion of fibrinogen decreases BMP signaling and enhances remyelination in vivo. Targeting fibrinogen may be an upstream therapeutic strategy to promote the regenerative potential of CNS progenitors in diseases with remyelination failure.

Keywords: NG2 cells; ancrod; cell fate; fibrin; myelin; neonatal brain injury; neuroinflammation; regeneration; stem/progenitor cells; vasculature.

MeSH terms

Activin Receptors, Type I / drug effects
Activin Receptors, Type I / genetics
Activin Receptors, Type I / metabolism
Animals
Blood Vessels / drug effects
Blood Vessels / pathology
Bone Morphogenetic Proteins / metabolism*
Fibrinogen / antagonists & inhibitors
Fibrinogen / pharmacology*
Lysophosphatidylcholines / pharmacology
Mice
Mice, Inbred C57BL
Mice, Knockout
Microarray Analysis
Myelin Sheath / metabolism
Oligodendrocyte Precursor Cells / drug effects
Oligodendrocyte Precursor Cells / metabolism*
Plasmids / genetics
Remyelination / drug effects*
Signal Transduction / drug effects

Substances

Bone Morphogenetic Proteins
Lysophosphatidylcholines
Fibrinogen
Activin Receptors, Type I
Acvr1 protein, mouse

Abstract

MeSH terms

Substances

Grants and funding